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At least 379 records · Page 21Linked to original sources
PubMed2003

Mutation of the Notch 3 gene in a Thai cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy family.

The authors report the first Thai family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in which the family members had a classical history of progressive vascular dementia. The proband was a 31-year old Thai male who presented with an acute stroke in the subcortical region. His past history revealed mental disturbance, including poor judgement and regressive behavior as well as mood changes for 1 year. He did not have a history of migraine or any other vascular risk factors except for a strong family history of ischemic stroke and progressive dementia. Magnetic resonance imaging demonstrated multiple small infarctions in the subcortical white matter of the bilateral frontal, parietal and occipital lobes with another small lesion in the pons. Genetic study demonstrated a Notch 3 mutation consisting of the substitution of a nucleotide at position 406 in exon 3 leading to the replacement of an Arginine by Cysteine at position 110 in the 2nd EGF motif, which is compatable with CADASIL.

Adult↗
PubMed2003

[Hereditary cerebral arteriopathy].

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) is a neurovascular disease caused by mutations of the notch3 gene, manifesting with strokes or stroke-like episodes, psychiatric symptoms, migraine and dementia. The diagnosis can be confirmed by screening exons of this gene. Involvement of the anterior temporal lobe and external capsule on MRI and presence of granular osmiophilic material on skin biopsy may help in diagnosis. We present two Norwegian families with eight members who have symptoms indicating CADASIL. The mutation R182C was demonstrated in exon 4 in seven; one refused gene testing. Two brothers without symptoms also tested positively for this gene mutation.

Aged↗
PubMed2006

Physiology and pathology of notch signalling system.

Notch proteins encode a family of transmembrane receptors that are part of a signalling transduction system known as Notch signalling, an extremely conserved and widely used mechanism regulating programs governing growth, apoptosis and differentiation in metazoans. Notch signalling begins when the Notch receptor binds ligands and ends when the Notch intracellular domain enters the nucleus and activates transcription of target genes. This core pathway is subjected to a wide array of regulatory influences and protein-protein interactions and is correlated with other signalling pathway. This review will summarize recent findings concerning the physiology and pathology of Notch signalling in vascular development and homeostasis. Moreover, the clinical phenotypes of Notch3 signalling system pathology will be described, with particular regard to CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) for which the most recent pathogenetic hypotheses are reported.

Animals↗
PubMed2005

Migraine and white matter hyperintensities.

Patients with migraine are at increased risk for white matter hyperintensities detected on magnetic resonance imaging. The presence of nonspecific white matter hyperintensities may cause uncertainty for physicians and anxiety for patients. The pathophysiology and long-term consequences of these lesions are unknown. Occasionally, white matter lesions in a migraineur may indicate an underlying disease such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), or central nervous system vasculitis. The ability to distinguish between nonspecific and disease-specific patterns of white matter hyperintensities in migraine sufferers is important for the practicing clinician.

Brain↗
PubMed2005

Genetics of cerebrovascular disorders.

Physicians must be able to recognize stroke caused by a mendelian or mitochondrial disorder. Some genetic disorders such as sickle cell anemia and Fabry disease have proven disease-specific treatments, whereas others have no effective treatment, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Proper diagnosis of a genetic disorder has prognostic value and prevents patient exposure to unnecessary and potentially harmful therapeutic agents and diagnostic tests. This article reviews the clinical and genetic features of some mendellan and mitochondrial disorders associated with ischemic stroke, hemorrhagic stroke, and cerebrovascular malformations.

Acidosis, Lactic↗
PubMed2003

Monogenic causes of stroke.

Monogenic disorders account for only a minority of strokes. Yet, they have been particularly helpful in exploring basic disease mechanisms. This article summarizes some recent data on monogenic stroke while focusing on two conditions: CADASIL, as a genetic variant of ischemic small vessel disease, and familial forms of cerebral amyloid angiopathy, which share many properties with sporadic disease.

Aged↗
PubMed2003

Small vessel disease: neuropathology.

Diseases of small cerebral blood vessels are heterogeneous in etiology and manifestations. Lipohyalinosis, venous collagenosis, amyloid angiopathy, and CADASIL affect different populations of blood vessels. Large and small hemorrhages, lacunae, cortical microinfarcts, and leukoaraiosis are the most important consequences of the small vessel angiopathies. Altered permeability as well as ischemia may be involved in the pathogenesis of the latter.

Aged↗
PubMed2003

Potential biological markers for cerebrovascular disease.

Cerebrovascular diseases can causes cognitive impairment and dementia by loss of neurons and synaptic connections, destruction of axons, and demyelinization. Biological markers including genetic tests, brain imaging techniques, and biochemical assays in the CSF are valuable for the identification and quantification of cerebrovascular diseases. Genetic tests may be used to detect mutations that cause hereditary cerebral amyloid angiopathies or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Structural CT and MR imaging is routinely used to visualize and quantify infarcts and white-matter changes. Functional SPET and PET imaging can demonstrate focal and remote effects of vascular lesions on cerebral blood flow and metabolism. Biochemical imaging using proton MRS is a nonspecific marker for neuronal and axonal damage. Among biochemical markers in the CSF, tau protein, phospho-tau, and beta amyloid protein are helpful to differentiate vascular dementia from Alzheimer's disease.

Aged↗
PubMed2003

Cognitive syndrome(s) in preclinical and clinical vascular dementia.

It is still a challenge to identify typical features of cognitive function in vascular dementia (VaD) in clinical as well as in preclinical stages. Selective empirical findings are described to illuminate degrees of cognitive decline. In predementia stages, speeded performance (motor and mental) and executive functions may be affected as demonstrated by CADASIL subjects and stroke survivors. In dementia stages, motor and mental speed as well as executive functions is commonly affected in addition to typical cognitive dysfunction in dementia (memory, verbal, and visuospatial). To summarize characteristics during preclinical and clinical stages, VaD appears to be associated with impairment in motor and mental speed as well as in executive function.

Aged↗
PubMed2006

Ischemic demyelination.

White matter lesions representing ischemic demyelination have evolved in terms of our understanding of their pathogenesis and potential clinical significance. Low density lesions on CT brain scan, most commonly seen in the periventricular region, also frequently seen in the centrum semiovale, have been termed 'leukoaraiosis'. In the past years, it was not uncommon at all to hear the term 'Binswanger's disease' used in an attempt to define the neurological sequelae of such lesions. Further refinement came with the advent of magnetic resonance imaging (MRI) brain scan which is particularly sensitive to such white matter areas of increased signal intensity, which tend to be seen particularly well on T2-weighted and fluid attenuation inversion recovery (FLAIR) scans. The major challenge has been to correlate the clinical attributes with such relatively frequent findings in the elderly population. Recent studies have looked at lesion load in a fashion analogous to that seen with multiple sclerosis. A particularly relevant clinical model for white matter disease is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) which combines the potential components of small vessel disease, resulting in progressive neurological deficit, with a common association with migraine which can also be associated with white matter lesions. However, the most common pathogenic factor associated with the microangiopathy, which appears to be at the heart of ischemic demyelination, continues to be hypertension. How well we are able to tie in the various pathological mechanisms associated with this end organ damage of the brain will determine how well we can arrive at effective interventions for a common contributor to neurological deficits in the elderly.

Brain↗
PubMed2005

[Genetic analysis of migraine headache: a review].

Recent advances in genetic analysis of migraine headache are reviewed. Point mutations of P/Q -type Ca2+ channel alpha1 subunit(CACNA1A) gene and Na-K ATPase, alpha2 (ATP1A2) gene have been identified in the familial hemiplegic migraine (FHM-1 and FHM-2, respectively). Mutations in notch-3 gene cause the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is an autosomal dominant inherited disorder often accompanying with migraine like headache. Serotonin (5-HT) related genes, dopamine D2 receptors (DRD2) gene, methylenetetrahydrofolate reductase (MTHFR) gene, and angiotensin converting enzyme (ACE) gene have been noticed as the susceptible genes for migraine pathogenesis. Genetic study of migraine is promising and will provide further understanding of the migraine pathophysiology. Discovery of the responsible or susceptible genes will open an avenue to develop new therapeutic strategy.

CADASIL↗
PubMed2005

[Neuropathology associated with dementia].

As dementing diseases are too numerous to refer to all of them, I confine my description to the neuropathology of amyotrophic lateral sclerosis with dementia (ALSD), and cerebral vascular pathology of three unique vascular diseases causing dementia. 1) ALSD: The cortical neuropathology of this condition exhibit two main unique profiles in addition to mainly temporal lobe-located cortical changes. One is ubiquitin-positive intraneuronal cytoplasmic inclusions, and the other a localized neuronal degeneration in the transitional zone between the hippocampal CA1 and subiculum. 2) Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): The characteristic vascular change of this condition is marked intimal thickening of the middle and small arteries with relatively preserved smooth muscle cells in the media. The scalp arteries escape this lesion, indicating non-ischemic pathomechanisms for the baldness seen in this condition. 3) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): The main lesions of the cerebral vessels are smooth muscle cell degeneration of deep perforating and small meningeal arteries with deposition of granular osomiophilic material in the media of the affected vessels. 4) Sneddon syndrome: This condition characterized by livedo reticularis and recurrent multiple infarctions shows marked sclerotic changes in the deep perforating arterioles and main cerebral arteries with relatively spared middle- and small-sized meningeal arteries.

Amyotrophic Lateral Sclerosis↗
PubMed2002

Investigation of Notch3 as a candidate gene for bipolar disorder using brain hyperintensities as an endophenotype.

The purpose of the study was to consider MRI hyperintensities as a potential endophenotype for bipolar disorder (BPD) and to investigate Notch3 (CADASIL) as a candidate gene for BPD. MRI scans were performed on 21 members of a family with a high incidence of BPD. Two-point and multipoint linkage analyses were performed and two exons of Notch3 were investigated with SSCP. Fifteen of 21 family members had MRI hyperintensities, including all bipolar patients and six family members with no affective illness. Two-point linkage analysis yielded negative results for all models. Multipoint linkage analysis yielded negative results except for Model 1a, in which a maximal LOD score was -1.24. A mutation screen of Exons 3 and 4 was negative. Notch3 does not appear to be a candidate gene for BPD in this family.

Adolescent↗
PubMed2004

Notch function in the vasculature: insights from zebrafish, mouse and man.

Vascular development entails multiple cell-fate decisions to specify a diverse array of vascular structures. Notch proteins are signaling receptors that regulate cell-fate determination in a variety of cell types. The finding that Notch genes are robustly expressed in the vasculature suggests roles for Notch in guiding endothelial and associated mural cells through the myriad of cell-fate decisions needed to form the vasculature. In fact, mice with defects in genes encoding Notch, Notch ligands, and components of the Notch signaling cascade invariably display vascular defects. Human Notch genes are linked to Alagille's Syndrome, a developmental disorder with vascular defects, and CADASIL, a cerebral arteriopathy. Studies in zebrafish, mice and humans indicate that Notch works in conjunction with other angiogenic pathways to pattern and stabilize the vasculature. Here, we will focus on established functions for Notch in vascular remodeling and arterial/venous specification and more speculative roles in vascular homeostasis and organ-specific angiogenesis.

Animals↗
PubMed1999

EGF-like domain calcium affinity modulated by N-terminal domain linkage in human fibrillin-1.

Calcium binding epidermal growth factor-like domains (cbEGFs) are present in many extracellular proteins, including fibrillin-1, Notch-3, protein S, factor IX and the low density lipoprotein (LDL) receptor, which perform a diverse range of functions. Genetic mutations that cause amino acid changes within these proteins have been linked to the Marfan syndrome (MFS), CADASIL, protein S deficiency, haemophilia B and familial hypercholesterolaemia, respectively. A number of these mutations disrupt calcium binding to cbEGFs, emphasising the critical functional role of calcium in these proteins. We have determined the calcium binding affinity of two sites within a cbEGF pair (cbEGF12-13) from human fibrillin-1 using two-dimensional nuclear magnetic resonance (NMR) and fluorescence techniques. Fibrillin-1 is a mosaic protein containing 43 cbEGF domains, mainly arranged as tandem repeats. Our results show that the cbEGF13 site in the cbEGF12-13 pair possesses the highest calcium affinity of any cbEGF investigated from fibrillin-1. A comparative analysis of these and previously reported calcium binding data from fibrillin-1 demonstrate that the affinity of cbEGF13 is enhanced more than 70-fold by the linkage of an N-terminal cbEGF domain. In contrast, comparison of calcium binding by cbEGF32 in isolation relative to when linked to a transforming growth factor beta-binding protein-like domain (TB6-cbEGF32) reveals that the same enhancement is not observed for this heterologous domain pair. Taken together, these results indicate that fibrillin-1 cbEGF Ca2+ affinity can be significantly modulated by the type of domain which is linked to its N terminus. The cbEGF12-13 pair is located within the longest contiguous section of cbEGFs in fibrillin-1, and a number of mutations in this region are associated with the most severe neonatal form of MFS. The affinities of cbEGF domains 13 and 14 in this region are substantially higher than in the C-terminal region of fibrillin-1. This increased affinity may be important for fibrillin assembly into 10-12 nm connective tissue microfibrils and/or may contribute to the biomechanical properties of the microfibrillar network.

Binding Sites↗
PubMed1998

Notch signalling pathway and human diseases.

Several homologs of the Drosophila Notch receptor and its ligands, Delta/Serrate, have been cloned in man. Three human disorders including a neoplasia (a T-cell acute lymphoblastic leukemia/lymphoma), a late onset neurological disease (CADASIL) and a developmental disorder (the Alagille syndrome) are associated with mutations in, respectively, the Notch1, Notch3 and Jagged1 genes, pointing out the broad spectrum of Notch activity in humans. We report herein on what has been learned on the role of these human Notch genes and the mechanisms leading from mutations in those genes to the observed phenotypes.

Alagille Syndrome↗
PubMed1998

Difficulties in the clinical diagnosis of vascular dementia and dementia of the Alzheimer type--comparison of clinical classifications.

The article compares the diagnostic criteria of dementia (DSM-III-R; DSM-IV; ICD-10; NINCDS-ADRDA; CERAD), dementia of the Alzheimer type (DSM-III-R; DSM IV; ICD-10; NINCDS-ADRDA; CERAD) and vascular dementia (DSM-III-R; DSM IV; ICD-10; NINDS-AIREN and ADDTC). There are major differences with respect to the definition of dementia, minor differences with respect to the definition of DAT and major disagreement concerning the definition of vascular dementia resulting in significant variability in the prevalence of the respective disorders. In patients with leukaraiosis and subcortical infarcts the differentiation of vascular and degenerative dementias is particularly difficult. In these cases onset and progression of dementia are often gradual and focal signs and symptoms are not always found. "New diagnoses" such as dementia with Lewy bodies, hippocampal sclerosis. CADASIL and dementia lacking distinctice histological features should be considered.

Alzheimer Disease↗
PubMed2004

[Diagnosis and differential cerebral vasculitis diagnosis].

Over a 5-year period, we investigated 77 consecutive patients (36 males, 41 females, mean age 40.9 years) referred to our hospital with the diagnosis of CNS vasculitis. Extensive workup including MRI, echocardiography, laboratory tests, angiography ( n=53), and biopsies at appropriate sites ( n=26) was performed based on individual history and symptoms. Prominent symptoms were stroke ( n=61), encephalopathy ( n=14), and headaches ( n=2). Vasculitis was finally diagnosed in 13 patients (17%) including isolated angiitis of the CNS ( n=3), giant cell arteritis ( n=4), and septic arteritis ( n=3). Thirty-two patients (42%) presented noninflammatory vasculopathies including moyamoya ( n=6), Sneddon's syndrome ( n=5), dissection ( n=4), CADASIL ( n=2), and collagen vascular disease ( n=9). Coagulopathy was found in 14 cases (18%) including antiphospholipid syndrome ( n=8) and APC resistance ( n=4). Other causes were cardiogenic embolism ( n=8), multiple sclerosis ( n=5), and migraine stroke ( n=3). Only a minority of patients referred for evaluation of suspected CNS vasculitis actually present with inflammatory vascular disease. Main differential diagnosis includes noninflammatory vasculopathies, coagulopathies, and cardiac disease. Since septic processes may be responsible for the symptoms, "blind" treatment with immunosuppressive agents should be strictly avoided.

Adult↗